Crystal forms of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3,- dihydroxybutanedioate salts and method of production

ABSTRACT

The invention relates to crystal forms of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxy butanedioate salts having the formula shown below:  
                 
 
     and to pharmaceutical compositions containing the above compound, methods of treating hyperproliferative diseases, such as cancers, in mammals, especially humans by administering the above compound, and to methods of preparing the crystal forms of the above compound and related compounds.

BACKGROUND OF THE INVENTION

[0001] This invention relates to crystal forms of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate (1:1) salts having the formula shown below:

[0002] The invention further relates to a method of making6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxybutanedioate (1:1) salts. The compoundsof the present invention are useful in the treatment ofhyperproliferative diseases, such as cancers, in mammals, especiallyhumans. The invention further relates to pharmaceutical compositionscontaining such compounds.

[0003] The free base,6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,is described in co-pending U.S. Ser. No. 09/383,755, filed Aug. 26,1999, the disclosure of which is hereby incorporated herein by referencein its entirety. The foregoing application is assigned in common withthe present application. The aforementioned free base is useful in thetreatment of hyperproliferative diseases such as cancers.

SUMMARY OF THE INVENTION

[0004] The present invention relates to crystalline tartrate salts of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-onehaving the formula shown below:

[0005] Two crystal forms of formula I have been identified. The crystalforms of formula I are herein referred to as crystal form A and crystalform B. Crystal form A is an anhydrous crystalline salt of formula I,while crystal form B is a sesquihydrate crystalline salt of formula I.

[0006] The present invention relates to6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate salts. The6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-onehas a chiral center at the 6-postion. Thus, the free base,6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,may have specific rotations of (+) or (−). The tartrate salt may beL-tartaric acid or D-tartaric acid. L-tartaric acid is also known as(2R,3R)-(+)-tartaric acid, while D-tartaric acid is (2S,3S)-(−)-tartaricacid. Both acids are available from Aldrich Chemical Company, Inc.,Milwaukee, Wis.

[0007] Particularly preferred salts include(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate salt and(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate salt. Other particularly preferred saltsinclude6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate salt and6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate salt.

[0008] More particularly preferred salts include(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate salt and(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate salt. The salts of the present inventionmay be present in anhydrous or hydrous form.

[0009] The present invention further relates to(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate salt. The invention also relates to(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate salt.

[0010] The present invention further comprises pharmaceuticalcompositions of crystal forms A and B of the compound of formula I and amethod for the production of crystal forms A and B of the compound offormula I.

[0011] It is a further object of the present invention to providecrystal forms A and B in a pharmaceutically orally administeredcomposition. Crystal forms A and B of the compound of formula I areuseful for the oral administration of the drug in solid form, such astablets. Crystal form A is preferred for use in the preparation ofpharmaceutical compositions containing the compound of formula I intablet form for oral administration.

[0012] Crystal forms A and B have been characterized by powder X-raydiffractometry. The anhydrous crystal form of the present invention isidentified in this application as crystal form A. The second crystalform of formula I is a sesquihydrate having approximately 5.5% water andis identified herein as crystal form B.

[0013] The anhydrous crystal form A of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate is characterized by high-intensitydiffraction peaks at diffraction angles (2θ) of about 3.6, 17.2, 17.6,18.8, 19.2, 20.4 and 22.1 in a powder X-ray diffraction pattern.Furthermore, the anhydrous crystal form A of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate provides a powder X-ray diffractionpattern substantially the same as the X-ray diffraction pattern shown inGraph 1, below. The experimental conditions under which the powder X-raydiffraction was conducted are as follows: Cu anode; wavelength 1:1.54056; wavelength 2: 1.54439 (Rel Intensity: 0.500); range # 1 -coupled: 3.000 to 40.000; step size: 0.040; step time: 1.00; smoothingwidth: 0.300; and threshold: 1.0. The characteristic diffraction peaksat diffraction angles (2θ) in a powder X-ray diffraction analysis forthe crystal form A are shown in Table 1.

[0014] The hydrate crystal form B of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate is characterized in that the crystalprovides high-intensity diffraction peaks at diffraction angles (2θ) ofabout 5.1, 8.1, 18.2, 18.8, 20.2, 20.8, 23.6, 25.8 and 26.0 in a powderX-ray diffraction pattern. Furthermore, the hydrate crystal form B of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate provides a powder X-ray diffractionpattern substantially the same as the powder X-ray diffraction patternshown in Graph 2, below. The experimental conditions under which thepowder X-ray diffraction was conducted are as follows: Cu anode;wavelength 1: 1.54056; wavelength 2: 1.54439 (Rel Intensity: 0.500);range # 1 - coupled: 3.000 to 40.000; step size: 0.040; step time: 1.00;smoothing width: 0.300; and threshold: 1.0. The characteristicdiffraction peaks at diffraction angles (2θ) in a powder X-raydiffraction analysis for crystal form B are shown in Table 2.

[0015] The characteristic d-spacings, intensities, and 2-theta (2θ)values for the diffraction pattern of crystal forms A and B are shownbelow in Tables 1 and 2, respectively. TABLE 1 Crystal Form A d- d-Angle value I* Angle value I* Angle d-value I* 2 theta Å (rel.) 2 thetaÅ (rel.) 2 theta Å (rel.) 3.6 24.7 100 16.9 5.3 1.3 23.4 3.8 2.4 6.214.2 3.3 17.2 5.2 9.7 25.1 3.5 3.7 7.2 12.3 1.9 17.6 5.1 9.2 25.5 3.52.0 9.5 9.3 1.5 18.8 4.7 5.6 26.0 3.4 1.5 10.8 8.2 1.7 19.2 4.6 5.2 26.73.3 2.2 12.3 7.2 1.2 19.7 4.5 2.0 27.6 3.2 1.8 12.5 7.1 1.4 20.4 4.410.0 28.2 3.2 2.0 13.8 6.4 1.3 21.7 4.1 1.3 28.5 3.1 2.1 14.5 6.1 1.422.1 4.0 6.0 29.0 3.1 1.8 16.0 5.5 4.8 22.6 3.9 2.2 29.9 3.0 2.0

[0016] TABLE 2 Crystal Form B d- d- Angle value I* Angle value I* Angled-value I* 2-theta Å (rel.) 2-theta Å (rel.) 2-theta Å (rel.) 5.1 17.245 19.9 4.5 28.5 26.0 3.4 42.9 8.1 10.9 30 20.2 4.4 45.3 26.7 3.3 10.412.7 7.0 10.1 20.8 4.3 100 27.6 3.2 11.0 13.9 6.4 20.7 21.4 4.2 20.328.1 3.2 10.5 14.6 6.1 28.0 21.7 4.1 16.5 28.7 3.1 13.4 15.2 5.9 17.222.8 3.9 20.8 30.2 3.0 25.9 15.3 5.8 11.9 23.6 3.8 39.3 31.2 2.9 10.316.4 5.4 20.6 24.1 3.7 19.2 32.1 2.8 16.6 16.8 5.3 12.1 24.4 3.6 19.633.1 2.7 11.2 18.2 4.9 29.3 24.8 3.6 13.2 34.4 2.6 10.1 18.8 4.7 57.725.5 3.5 13.2 36.8 2.4 9.4 19.3 4.6 9.6 25.8 3.5 42.3 37.4 2.4 9.4

[0017] It is to be understood that the powder X-ray diffraction patternis only one of many ways to characterize the arrangement of atomscomprising6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate and that other methods well known in the art,e.g. single crystal X-ray diffraction, Near Infrared Spectroscopy, etc.may be used to identify crystal forms A and B.

[0018] The present invention relates to a compound which is crystal formA of the compound(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-i-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate or(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate that exhibits a powder X-ray diffractionpattern having characteristic peaks expressed in degrees 2-theta atapproximately 3.6, 6.2, 7.2, 9.5, 10.8, 17.2, 17.6, 19.2, and 22.1. Thisinvention also relates to a crystal of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate or(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate that exhibits a powder X-ray diffractionpattern having characteristic peaks expressed in degrees 2-theta atapproximately the values shown in Table 1 above.

[0019] The present invention relates to a compound which is crystal formB of the compound(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate or(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate that exhibits a powder X-ray diffractionpattern having characteristic peaks expressed in degrees 2-theta atapproximately 5.1, 8.1, 16.4, 18.2, 20.8, 21.4, 21.7, 24.4, 30.2, 32.1,36.8 and 37.4. This invention also relates to a crystal of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate or(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate that exhibits a powder X-ray diffractionpattern having characteristic peaks expressed in degrees 2-theta atapproximately the values shown in Table 2 above.

[0020] The invention also relates to a process for the preparation ofthe compounds of the formula I. The free base of formula I is preparedaccording to the manner described in Example 1. The free base has onechiral carbon at the 6-position. Example 2 discloses the method andprocess for preparation and separation the two enantiomers of the freebase,6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one.The faster eluting enantiomer A causes the plane of polarization torotate in counterclockwise (negative) direction, i.e., (−) enantiomer.While, the slower moving enantiomer B causes the plane of polarizationto rotate in clockwise (positive) direction, i.e., (+) enantiomer.

[0021] The tartrate salts of the compound of formula I are made bymixing desired tartaric acid (i.e., D or L) with the free base6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one.The free base may be either the (−) or (+) enantiomer. The reaction toform crystal form B is done in a mixed solvent system, such asTHF/water. Recrystallization of the tartaric salt of formula I in anorganic solvent, such as ethyl acetate, at elevated temperatures resultsin the isolation of crystal form A.

[0022] In one preferred embodiment crystal form B is prepared accordingto the method comprising the steps of (i) charging a flask with freebase of the compound of formula I and a solvent; (ii) addition of thetartrate salt to the free base solution followed by stirring to form athick slurry; and (iii) isolation of the solids by filtration followedby drying. The aforementioned method to prepare crystal form B may bemodified to make crystal form A. Following formation of the thick slurryin step (ii) dry ethyl acetate is added to the reaction flask and thestirred supension is atmospherically distilled. As solvent is distilledoff fresh ethyl acetate is added, followed by distillation to a smallvolume. The reaction mixture is then granulated at ambient temperaturefollowed by isolation of the solids (crystal form A) using filtrationand vacuum drying.

[0023] Crystal form A of the present invention can be produced fromisolated crystal form B. Crystal form A is produced by the steps of (i)heating the crystalline form B in an organic solvent, such as ethylacetate; (ii) removing the water azeotropically followed by replacementwith dry ethyl acetate; (iii) removing the solvent under atmosphericconditions to isolate the solids; and (iv) washing the solids usingethyl acetate and subjecting the product to vacuum drying at elevatedtemperatures, e.g., 40° C. Note that it is also possible to remove thesolvent in step (iii) under vacuum.

[0024] Crystal form A of the present invention may also be prepareddirectly without isolation of the crystal form B. For example, crystalform A may be produced by refluxing at 80° C.-82° C. for 1-hour amixture of the free base of the compound of formula I (approximately 1.3equivalents) with the tartrate salt in hot 2B ethanol (20 volume). Themixture is allowed to cool to room temperature slowly followed bystirring overnight. The solvent is then removed under atmosphericconditions and the isolated solid is dried.

[0025] The salts of the present invention may exist in amorphous form.Although, such forms may be unstable. However, such salts may beconverted to crystalline forms according to methods well known to thoseof ordinary skill in the art, e.g., heating, etc.

[0026] It is to be understood that the methods described herein are onlyexemplary and are not intended to exclude variations in the aboveparameters which allow the production of crystal forms A and B invarying granulations and yields, according to the desired storage,handling and manufacturing applications of the compound. Crystal formsof the present invention may be further processed, such as granulationor milling, to form microcrystalline material suitable for bulkmanufacturing purposes.

[0027] The crystal forms A and B can be characterized using powder X-raydiffractometry.

[0028] This invention also relates to a method for the treatment ofabnormal cell growth in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula I,as defined above, a prodrug or solvate thereof, that is effective ininhibiting farnesyl protein transferase. In one embodiment of thismethod, the abnormal cell growth is cancer, including, but not limitedto, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, uterine cancer,ovarian cancer, rectal cancer, cancer of the anal region, stomachcancer, colon cancer, breast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer ofthe urethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said method, said abnormal cell growth is a benignproliferative disease, including, but not limited to, psoriasis, benignprostatic hypertrophy or restinosis.

[0029] This invention also relates to a method for the treatment ofabnormal cell growth in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula I,as defined above, a prodrug or solvate thereof, that is effective intreating abnormal cell growth.

[0030] This invention also relates to a method for the treatment ofabnormal cell growth in a mammal which comprises administering to saidmammal a therapeutically effective amount of a compound of formula I, aprodrug or solvate thereof, in combination with an anti-tumor agentselected from the group consisting of mitotic inhibitors, alkylatingagents, anti-metabolites, intercalating antibiotics, growth factorinhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors,biological response modifiers, anti-hormones, and anti-androgens.

[0031] The present invention also relates to a method for the treatmentof an infection in a mammal, including a human, that is facilitated byfarnesyl protein transferase, such as hepatitus delta virus or malaria,which comprises administering to said mammal a therapeutically effectiveamount of a compound of formula I as defined above, a prodrug or solvatethereof.

[0032] This invention also relates to a pharmaceutical composition forthe treatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the formula I, as defined above, aprodrug or solvate thereof, that is effective in inhibiting farnesylprotein transferase, and a pharmaceutically acceptable carrier. In oneembodiment of said composition, said abnormal cell growth is cancer,including, but not limited to, lung cancer, bone cancer, pancreaticcancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, carcinoma of the cervix, carcinoma of the vagina, carcinomaof the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland,sarcoma of soft tissue, cancer of the urethra, cancer of the penis,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of theforegoing cancers. In another embodiment of said pharmaceuticalcomposition, said abnormal cell growth is a benign proliferativedisease, including, but not limited to, psoriasis, benign prostatichypertrophy or restinosis.

[0033] This invention also relates to a pharmaceutical composition forthe treatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the formula I, as defined above, aprodrug or solvate thereof, that is effective in treating abnormal cellgrowth, and a pharmaceutically acceptable carrier.

[0034] The invention also relates to a pharmaceutical composition forthe treatment of abnormal cell growth in a mammal, including a human,which comprises a therapeutically effective amount of a compound offormula I, as defined above, a prodrug or solvate thereof, incombination with a pharmaceutically acceptable carrier and an anti-tumoragent selected from the group consisting of mitotic inhibitors,alkylating agents, anti-metabolites, intercalating antibiotics, growthfactor inhibitors, cell cycle inhibitors, enzymes, topoisomeraseinhibitors, biological response modifiers, anti-hormones, andanti-androgens.

[0035] This invention also relates to a pharmaceutical composition forthe treatment of an infection in a mammal, including a human, that isfacilitated by farnesyl protein transferase, such as malaria orhepatitus delta virus, comprising an amount of a compound of the formulaI, as defined above, a prodrug or solvate thereof, that is effective intreating abnormal cell growth, and a pharmaceutically acceptablecarrier.

[0036] “Abnormal cell growth”, as used herein, unless otherwiseindicated, refers to cell growth that is independent of normalregulatory mechanisms (e.g., loss of contact inhibition). This includesthe abnormal growth of: (1) tumor cells (tumors) expressing an activatedRas oncogene; (2) tumor cells in which the Ras protein is activated as aresult of oncogenic mutation in another gene; (3) benign and malignantcells of other proliferative diseases in which aberrant Ras activationoccurs; and (4) any tumors that proliferate by virtue of farnesylprotein transferase.

[0037] The term “treating”, as used herein, unless otherwise indicated,means reversing, alleviating, inhibiting the progress of, or preventingthe disorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

DETAILED DESCRIPTION OF THE INVENTION

[0038] The present invention relates to crystal forms of the followingcompound:

[0039] The present invention further relates to the two distinct crystalforms of the compound of formula I. The compound of formula I has beenfound to have two crystal forms, one form is an anhydrous, while thesecond is a sesquihydrate. The anhydrous crystal form of the compound offormula I is referred herein as crystal form A. The sesquihydratecrystal form of the compound of formula I is referred herein as crystalform B.

[0040] The invention further relates to a method for the preparation ofthe crystal forms of compound of formula I. Formula I is also identifiedherein as6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxybutanedioate (1:1). The free base,6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,has a chiral center at its 6-position and the enantiomers can rotate theplane of polarization in a clockwise (+) or counterclockwise (−)direction.

[0041] The compounds of the present invention are useful in thetreatment of hyperproliferative diseases, such as cancers, in mammals,especially humans, and to pharmaceutical compositions containing suchcompounds.

[0042] The tartrate salt of the compound of formula I has unexpectedlyfound to have improved solubility in gastric fluids compared to othersalts of the compound of formula I, i.e., HCl. Improved solubility ingastric fluids will make the tartrate salt of the compound of formula Imore readily bioavailable when administered in tablet form.

[0043] The crystal forms of the compound of formula I have beencharacterized using powder X-ray diffractometry. The powder X-raydiffraction pattern for enantiomer pairs(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxybutanedioate and(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxybutanedioate or(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxybutanedioate and(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxybutanedioate will be the same.

[0044] Crystal form A of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxybutanedioate provides a powder X-ray diffractionpattern substantially the same as shown in Graph 1. Crystal form B of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxybutanedioate provides a powder X-ray diffractionpattern substantially the same as shown in Graph 2. However, it is knownthat a powder X-ray diffraction pattern may be obtained with ameasurement error depending on measurement conditions. In particular, itis generally known that intensities in a powder X-ray diffractionpattern may fluctuate depending on measurement conditions. Therefore, itshould be understood that the crystal forms of the present invention arenot limited to the crystals that provide a powder X-ray diffractionpattern completely identical to the powder X-ray diffraction patternsshown in Graphs 1 and 2. Any crystal forms of formula I which provide apowder X-ray diffraction pattern substantially the same as theaforementioned powder X-ray diffraction patterns of Graphs 1 and 2 fallwithin the scope of the present invention. Those skilled in the field ofpowder X-ray diffractometry can readily judge the substantial identityof powder X-ray diffraction patterns.

[0045] For example, the crystal form A of the present invention ischaracterized in that the crystal provides a high intensity diffractionpeak at diffraction angle (2θ) of about 3.6 in a powder X-raydiffraction analysis. Generally, a measurement error of diffractionangle for a usual powder X-ray diffractometry is about 5% or less, andsuch degree of measurement error should be taken into account as to theaforementioned diffraction angles. Furthermore, it should be understoodthat relative intensities may fluctuate depending on experimentalconditions as described above, and accordingly, the order of intensityshould not be taken into account.

[0046] The compounds of formula I exhibit activity as Ras farnesylationinhibitors and are useful in the treatment of cancer and the inhibitionof abnormal cell growth in mammals, including humans. The activity ofthe compounds of formula I as Ras farnesylation inhibitors may bedetermined by their ability, relative to a control, to inhibit Rasfarnesyl transferase in vitro. This procedure is described below.

[0047] A crude preparation of human farnesyl transferase (FTase)comprising the cytosolic fraction of homogenized brain tissue is usedfor screening compounds in a 96-well assay format. The cytosolicfraction is prepared by homogenizing approx. 40 grams fresh tissue in100 ml of sucrose/MgCl₂/EDTA buffer (using a Dounce homogenizer; 10-15strokes), centrifuging the homogenates at 1000 grams for 10 minutes at4G, re-centrifuging the supernatant at 17,000 grams for 15 minutes at4G, and then collecting the resulting supernatant. This supernatant isdiluted to contain a final concentration of 50 mM Tris HCl (pH 7.5), 5mN DTT, 0.2 M KCl, 20 mM ZnCl₂, 1 mM PMSF and re-centrifuged at 178,000grams for 90 minutes at 4G. The supernatant, termed “crude FTase” wasassayed for protein concentration, aliquoted, and stored at −70° C.

[0048] The assay used to measure in vitro inhibition of human FTase is amodification of the method described by Amersham LifeScience for usingtheir Farnesyl transferase (3H) Scintillation Proximity Assay (SPA) kit(TRKQ 7010). FTase enzyme activity is determined in a volume of 100 mlcontaining 50 mM N-(2-hydroxy ethyl) piperazine-N-(2-ethane sulfonicacid) (HEPES), pH 7.5, 30 mM MgCl₂, 20 uM KCl, 5 mM Na₂HPO₄, 5 mMdithiothreitol (DTT), 0.01% Triton X-100, 5% dimethyl sulfoxide (DMSO),20 mg of crude FTase, 0.12 mM [3H]-farnesyl pyrophosphate ([3H]-FPP;36000 dpm/pmole, Amersham LifeScience), and 0.2 mM of biotinylated Raspeptide KTKCVIS (Bt-KTKCVIS) that is N-terminally biotinylated at itsalpha amino group and was synthesized and purified by HPLC in house. Thereaction is initiated by addition of the enzyme and terminated byaddition of EDTA (supplied as the STOP reagent in kit TRKQ 7010)following a 45 minute incubation at 37° C. Prenylated and unprenylatedBt-KTKCVIS is captured by adding 10 ml of steptavidin-coated SPA beads(TRKQ 7010) per well and incubating the reaction mixture for 30 minutesat room temperature. The amount of radioactivity bound to the SPA beadsis determined using a MicroBeta 1450 plate counter. Under these assayconditions, the enzyme activity is linear with respect to theconcentrations of the prenyl group acceptor, Bt-KTKCVIS, and crudeFTase, but saturating with respect to the prenyl donor, FPP. The assayreaction time is also in the linear range.

[0049] The test compounds are routinely dissolved in 100% dimethylsulfoxide (DMSO). Inhibition of farnesyl transferase activity isdetermined by calculating percent incorporation of tritiated-farnesyl inthe presence of the test compound vs. its incorporation in control wells(absence of inhibitor). IC₅₀ values, that is, the concentration requiredto produce half maximal farnesylation of Bt-KTKCVIS, is determined fromthe dose-responses obtained.

[0050] Administration of the compounds of the present invention (alsoreferred to herein as the “active compound(s)”) can be effected by anymethod that enables delivery of the compounds to the site of action.These methods preferably include oral routes such as in the form oftablets or capsules, intraduodenal routes, parenteral injection(including intravenous, subcutaneous, intramuscular, intravascular orinfusion), topical, and rectal administration. Oral administration ispreferred for the crystal Form A. Particularly preferred routes of oraladministration include tablets or capsules.

[0051] The amount of the active compound administered will be dependenton the subject being treated, the severity of the disorder or condition,the rate of administration and the judgement of the prescribingphysician. However, an effective dosage is in the range of about 0.001to about 100 mg per kg body weight per day, preferably about 1 to about35 mg/kg/day, in single or divided doses. For a 70 kg human, this wouldamount to about 0.05 to about 7 g/day, preferably about 0.2 to about 2.5g/day. In some instances, dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smalldoses for administration throughout the day.

[0052] The following examples illustrate preparation of free base offormula I, 6-[(4-chloro-phenyl)- and the tartrate crystalline forms ofthe free base. The examples are not intended to limited the invention asdefined hereinabove and as claimed below.

EXAMPLE 1

[0053]6-[(4-Chloro-Phenyl)-Hydroxy-(3-Methyl-3H-Imidazol-4-Yl)-Methyl]-4-(3-Ethynyl-Phenyl)-1-Methyl-1H-Quinolin-2-One

[0054] 1A.5-[2-(4-Chloro-Phenyl)-[1,3]Dioxolan-2-Yl]-3-(3-Iodo-Phenyl)-Benzo[c]Isoxazole

[0055] 2-(4-Chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane (38.7 g, 127mMol) was suspended in 190 mL of methanol (MeOH) under an atmosphere ofdry N₂. To this solution was added (3-iodophenyl)acetonitrile (46.3 g,190 mMol) and 25.4 g (625 mMol) of sodium hydroxide (NaOH). The solutionwas then heated to reflux and reacted at this temperature for 2 hours.The reaction mixture was cooled to ambient temperature and the MeOH wasremoved under vacuum. The resulting red oil was partitioned betweendichloromethane (DCM) and 0.1 N aqueous NaOH. The DCM layer was washedsuccessively with 0.1 N aqueous NaOH and then brine. The DCM layer wasdried over MgSO₄, filtered and concentrated under vacuum to give a darkred oil. The oil was stirred in MeOH and the titled compoundprecipitated out as a yellow solid. The yellow solid was washed withMeOH and dried under vacuum to give 52.4 g of the titled compound whichwas used without further purification.

[0056] 1B.[6-Amino-3-(4-Chloro-Benzoyl)-Cyclohexa-2,4-Dienyl]-(3-Iodo-Phenyl)-Methanone

[0057]5-[2-(4-Chloro-phenyl)-[1,3]dioxolan-2-yl]-3-(3-iodo-phenyl)-benzo[c]isoxazole(65.4 g, 130 mMol) was dissolved in a solution of tetrahydrofuran (THF)(500 mL) and DCM (100 mL). To this solution, was added 500 mL oftitanium(III) chloride (10 wt. % solution in 20-30 wt. % hydrochloricacid (HCl)) and the reaction mixture was stirred for 1 hour. Anadditional 100 mL of titanium(III) chloride (10 wt. % solution in 20-30wt. % HCl) was added to the reaction mixture and the reaction mixturewas stirred for 2.5 hours. The reaction mixture was then poured into icewater and the resulting heterogeneous solution was extracted with DCM.The DCM layer was successively washed with aqueous saturated NaHCO₃ andbrine. The DCM layer was dried over MgSO₄, filtered and concentratedunder vacuum to give titled compound as an orange oil (60 g). The oilwas used without further purification.

[0058] 1C. 6-(4-Chloro-Benzoyl)-4-(3-Iodo-Phenyl)-1H-Quinolin-2-One

[0059][6-Amino-3-(4-chloro-benzoyl)-cyclohexa-2,4-dienyl]-(3-iodo-phenyl)-methan-one(60 g, 130 mMol) was dissolved in anhydrous toluene (450 mL) under anatmosphere of dry N₂. To this solution was added 180 mL of triethylamine(NEt₃), 50 mL of acetic anhydride (Ac₂O) and 1.60 g (13.0 mMol) of4-dimethylaminopyridine (DMAP). The reaction mixture was then heated toreflux and stirred at this temperature for 20 hours. The reactionmixture was cooled to ambient temperature and the precipitate wascollected via suction filtration. The solid was washed with ethyl ether(Et₂O) and dried under vacuum to give of the titled compound (63 g)which was used without further purification.

[0060] 1D.6-(4-Chloro-Benzoyl)-4-(3-Iodo-Phenyl)-1-Methyl-1H-Quinolin-2-One

[0061] 6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1H-quinolin-2-one (63 g,130 mMol) was dissolved in THF (500 mL) under an atmosphere of dry N₂.To this solution, was added a 10 N aqueous NaOH (550 mL),benzyltriethylammonium chloride (13.8 g, 60.5 mMol) and methyl iodide(13.5 mL, 212.0 mMol). The reaction mixture was stirred at ambienttemperature for 15 hours after which time it was partitioned between DCMand water. The DCM layer was successively washed with water (4 times)and then brine. The organic layer was dried over MgSO₄, filtered andconcentrated under vacuum to give 51.2 g of a yellow solid as the titledcompound which was used without further purification.

[0062] 1E.6-(4-Chloro-Benzoyl)-1-Methyl-4-(3-Trimethylsilanylethynyl-Phenyl)-1H-Quinolin-2-One

[0063] 6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1-methyl-1H-quinolin-2-one(9.98 g, 20.0 mMol) was suspended in diethylamine (300 mL). To thissolution was added 50 mL of anhydrous N,N-dimethylformamide (DMF),(trimethylsilyl)acetylene (8.5 mL) andbis(triphenylphosphine)-palladium(II) chloride (1.40 g, 2.00 mMol). Theflask was covered with aluminum foil and then copper(I) iodide (780 mg,4.09 mMol) was added causing the reaction mixture to exotherm. Afterstirring overnight under an atmosphere of dry N₂ at ambient temperature,the reaction mixture was concentrated under vacuum and the residue waschromatographed on flash silica gel eluting with a gradient of DCM toMeOH/DCM (2:98) to give 8.55 g of the titled product as a solid.

[0064] 1F.6-[(4-Chloro-Phenyl)-Hydroxy-(2-Mercapto-3-Methyl-3H-Imidazol-4-Yl)-Methyl]-1-Methyl-4-(3-Trimethylsilanylethynyl-Phenyl)-1H-Quinolin-2-One

[0065] 2-Mercapto-1-methylimidazole (2.08 g, 18.2 mMol) was dissolved inanhydrous THF (200 mL) under an atmosphere of dry N₂. The solution wascooled to −78° C. and a solution of tert-butyl lithium (1.7 M inpentane, 22 mL, 37 mMol) was added. The solution was then warmed to 0°C. After a yellow precipitate formed, the solution was cooled to −78° C.and a solution of 6-(4-chloro-benzoyl)-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (8.55 g, 18.2 mMol) in anhydrous THF(25 mL) was added. After 30 minutes, the solution was warmed to 0° C.and stirred at this temperature for 1 hour. The reaction mixture wasthen warmed to ambient temperature and stirred overnight. The reactionwas quenched with 20 mL of saturated aqueous ammonium chloride (NH₄Cl)and then partitioned between DCM and water. The DCM layer was dried oversodium sulfate (Na₂SO₄), filtered and concentrated under vacuum. Theresidue was chromatographed on flash silica gel eluting with a gradientfrom DCM to MeOH/DCM (3:97) to give 5.0 g of the titled compound as asolid.

[0066] 1G.6-[(4-Chloro-Phenyl)-Hydroxy-(3-Methyl-3H-Imidazol-4-Yl)-Methyl]-1-Methyl-4-(3-Trimethylsilanylethynyl-Phenyl)-1H-Quinolin-2-One

[0067]6-[(4-Chloro-phenyl)-hydroxy-(2-mercapto-3-methyl-3H-imidazol-4-yl)-methyl]-l-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (5.0 g,8.6 mMol) was dissolved in ethanol (40 mL) to which was added Raney™nickel (ca. 10 g) and the reaction was heated to reflux. More RANEY™nickel was added every 20 minutes until mass spectral analysis of thereaction showed that the starting material had been consumed. Thereaction mixture was cooled to ambient temperature and filtered throughCELITE™ (diatomaceous earth). The CELITE™ was washed with copiousamounts of ethanol. The filtrates were combined and concentrated undervacuum to give 3.88 g of the titled compound.

[0068] C.I. m/z 552 [M+1]; ¹H NMR (CD₃OD) δ 7.64-7.75 (m, 3H), 7.17-7.48(m, 9 H), 6.59 (s, 1H), 6.17 (s, 1H), 3.79 (s, 3H), 3.42 (s, 3H), 0.23(s, 9H).

[0069] 1H.6-[(4-Chloro-Phenyl)-Hydroxy-(3-Methyl-3H-Imidazol-4-Yl)-Methyl]-4-(3-Ethynyl-Phenyl)-1-Methyl-1H-Quinolin-2-One

[0070]6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one(3.88 g, 7.03 mMol) was dissolved in THF (10 mL) under an atmosphere ofdry N₂. To this solution was added a solution of 1.0 Ntetrabutylammonium fluoride in THF (20 mL, 20 mMol). The reactionmixture was stirred overnight at ambient temperature and was thenconcentrated under vacuum. The residue was partitioned between4-(dicyanomethylene)-2-methyl-6-(4-dimethylamino-styryl)-4H-pyran (DCM)and water. The DCM layer was saved and washed 3 more times with waterand then with brine. The DCM layer was dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was chromatographed on flashsilica gel eluting with a gradient from DCM to MeOH/DCM (4:96) to give3.01 g of the titled compound.

[0071] C.l. m/z 480 [M+1]; ¹H NMR (CD₃OD) δ 7.75 (dd, J=2.1, 8.9 Hz,1H), 7.69 (s, 1H), 7.66 (d, 8.5 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.41(t, J=7.7 Hz, 1H), 7.38 (s, 1H), 7.29 (m, 3H), 7.23 (d, J=1.7 Hz, 1H),7.17 (d, J=8.5 Hz, 2H), 6.59 (s, 1H), 6.16 (s, 1H), 3.79 (s, 3H), 3.60(s, 1H), 3.42 (s, 3H).

EXAMPLE 2

[0072] Separation of the Enantiomers of6-[(4-Chloro-Phenyl)-Hydroxy-(3-Methyl-3H-Imidazol-4-Yl)-Methyl]-4-(3-Ethynyl-Phenyl)-1-Methyl-1H-Quinolin-2-One

[0073]6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one(4.96 g) was separated into its enantiomers and purified byhigh-performance liquid chromatography over CHIRALPAK™ AD (manufacturedby Daicel Chemical Industries, LTD, Osaka, Japan) (20 μm; eluent:Hexane/isopropanol/diethylamine 85/15/0.1; 30° C.). Under theseconditions, 1.73 g of the faster eluting enantiomer was obtained and2.07 g of the slower moving enantiomer B. The slower moving enantiomer Bhas a specific rotation ({α}_(D) ²⁰=+28.2 (c=10 mg/mL)) in ethanol. Bothenantiomers were >97% optically pure.

EXAMPLE 3

[0074](+)-6-[(4-Chloro-Phenyl)-Hydroxy-(3-Methyl-3H-Imidazol-4-Yl)-Methyl]-4-(3-Ethynyl-Phenyl)-1-Methyl-1H-Quinolin-2-One,(−)-2,3-DihydroxyButanedioate (1:1), (Crystal Form B)

[0075] A 125 ml flask was charged with 3.8 gms (7.92 mmoles) of(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-oneand 57 ml of THF 95%/water 5% by weight. The mixture was stirred until aclear amber solution was obtained. The amber solution was thenspeck-free filtered into a speck-free 125 ml flask. Then 1.55 gms (10.3mmoles) of D-(−)tartaric acid was added to the filtered solution whilestirring. After stirring for 20 hours a thick slurry had formed. Thesolids were isolated by filtration and the filter cake washed with 16mls of Ethyl acetate. The solids were dried by pulling vacuum on thefilter, a small sample is vacuum dried at 40° C. for analysis resultingin crystal form B having the powder X-ray diffraction pattern shown inGraph 2. Crystal form B was found to show plate/lath habit.

[0076] Using thermogravimetric analysis (TGA) form B lost approximately5.5% weight at a temperature below 100° C., which is close to aseqsquihydrate (5.3%). Additionally, crystal form B was characterized ashaving a dehydration endotherm of between 80° C. and 100° C. usingDifferential Scanning Calorimetry (DSC).

EXAMPLE 4

[0077](+)-6-[(4-Chloro-Phenyl)-Hydroxy-(3-Methyl-3H-Imidazol-4-Yl)-Methyl]-4-(3-Ethynyl-Phenyl)-1-Methyl-1H-Quinolin-2-One,(−)-2,3-Dihydroxy Butanedioate (1:1), (Crystal Form A)

[0078] The filter cake (Form B) from Example 3 was placed in a 500 mlflask and 160 mls of dry ethyl acetate was added and the stirredsuspension was atmospherically distilled. As solvent distilled off freshethyl acetate was added until a total of 320 mls of dry ethyl acetatehad been added, the final volume of the reaction was 80 mls. Thereaction mixture was granulated for 20 hrs at ambient temperature.

[0079] The solids were isolated by filtration and the filter cake washedwith 30 mls of ethyl acetate followed by vacuum drying at 40° C.,resulting in the recovery of crystal form A having the powder X-raydiffraction pattern shown in Graph 1.

[0080] Crystal form A was found to melt with a small endotherm followedby decomposition with an exotherm peak temperature of 189° C. by DSC.

What is claimed is:
 1. A crystal form of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate anhydrous salt.
 2. The crystal form accordingto claim 1, comprising high-intensity diffraction peaks at diffractionangles (2θ) of about 3.6, 17.2, 17.6, 18.8, 19.2, 20.4 and 22.1 in thepowder X-ray diffraction analysis.
 3. The crystal form according toclaim 2, comprising a powder X-ray diffraction pattern havingcharacteristic peaks expressed in degrees (2θ) at approximately: AngleAngle Angle 2 theta 2 theta 2 theta 3.6 16.9 23.4 6.2 17.2 25.1 7.2 17.625.5 9.5 18.8 26.0 10.8 19.2 26.7 12.3 19.7 27.6 12.5 20.4 28.2 13.821.7 28.5 14.5 22.1 29.0 16.0 22.6 29.9


4. The crystal form according to claim 3, wherein said salt has a powderX-ray diffraction pattern substantially the same as the powder X-raydiffraction pattern shown in Graph
 1. 5. The crystal form according toclaim 1, wherein said anhydrous salt is(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate.
 6. The crystal form according to claim 1,wherein said anhydrous salt is6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-i-methyl-1H-quinolin-2-one, (−)-2,3-dihydroxy butanedioate.
 7. Thecrystal form according to claim 5, wherein said anhydrous salt is(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate
 8. The crystal form according to claim 1,wherein said anhydrous salt is(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate.
 9. The crystal form according to claim 1,wherein said anhydrous salt is6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate.
 10. The crystal form according to claim9, wherein said anhydrous salt is(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate.
 11. The crystal form according to claim1, wherein said anhydrous salt has a melting point of 189° C.
 12. Acrystal form of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate hydrate salt.
 13. The crystal form accordingto claim 12, comprising high-intensity diffraction peaks at diffractionangles (2θ) of about 5.1, 8.1, 18.2, 18.8, 20.2, 20.8, 23.6, 25.8 and26.0 in the powder X-ray diffraction analysis.
 14. The crystal formaccording to claim 13, comprising a powder X-ray diffraction patternhaving characteristic peaks expressed in degrees (2θ) at approximately:Angle Angle Angle 2-theta 2-theta 2-theta 5.1 19.9 26.0 8.1 20.2 26.712.7 20.8 27.6 13.9 21.4 28.1 14.6 21.7 28.7 15.2 22.8 30.2 15.3 23.631.2 16.4 24.1 32.1 16.8 24.4 33.1 18.2 24.8 34.4 18.8 25.5 36.8 19.325.8 37.4


15. The crystal form according to claim 14, wherein said crystal formhas a powder X-ray diffraction pattern substantially the same as thepowder X-ray diffraction pattern shown in Graph
 2. 16. The crystal formaccording to claim 12, wherein said hydrate is(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-12-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate.
 17. The crystal form according to claim 12,wherein said hydrate is6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate.
 18. The crystal form according to claim17, wherein said hydrate is(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate
 19. The crystal form according to claim12, wherein said hydrate is(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate.
 20. The crystal form according to claim 12,wherein said hydrate is6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate.
 21. The crystal form according to claim20, wherein said hydrate is(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate
 22. A process for preparing a salt havingthe formula

comprising treating6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-onewith tartaric acid which provides high-intensity diffraction peaks atdiffraction angles (2θ) of 5.1, 8.1, 18.2, 18.8, 20.2, 20.8, 23.6, 25.8and 26.0 in the powder X-ray diffraction pattern.
 23. The process ofclaim 22, wherein said process is carried out in a mixture of THF andwater.
 24. The process of claim 22, wherein said salt is(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate hydrate salt.
 25. The process of claim22, wherein said salt is(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate hydrate salt.
 26. A process for preparing6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate anhydrous salt comprising azeotropic removalof water from6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,2,3-dihydroxy butanedioate hydrate salt.
 27. The process of claim 26,wherein said anhydrous salt is(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(−)-2,3-dihydroxy butanedioate anhydrous salt.
 28. The process of claim26, wherein said anhydrous salt is(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate anhydrous salt.
 29. A process forpreparing a salt having the formula

comprising treating6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-onewith tartaric acid in a polar solvent at an elevated temperature to forman anhydrous crystal form which provides high-intensity diffractionpeaks at diffraction angles (2θ) of about 3.6, 17.2, 17.6, 18.8, 19.2,20.4 and 22.1 in the powder X-ray diffraction pattern.
 30. The processof claim 29, wherein said salt is(+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-iH-quinolin-2-one, (−)-2,3-dihydroxy butanedioate anhydrous salt.
 31. Theprocess of claim 29, wherein said salt is(−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one,(+)-2,3-dihydroxy butanedioate anhydrous salt.
 32. The process of claim29, wherein the polar solvent is ethyl acetate.
 33. A method of treatinga hyperproliferative disorder in a mammal which comprises administeringto the mammal a therapeutically effective amount of a compound accordingto claim
 1. 34. The method of claim 33, wherein the method is for thetreatment of a cancer selected from brain, squamous cell, bladder,gastric, pancreatic, breast, head, neck, oesophageal, prostate,colorectal, lung, renal, kidney, ovarian, gynecological and thyroidcancer.
 35. A method for the treatment of a hyperproliferative disorderin a mammal which comprises administering to the mammal atherapeutically effective amount of a polymorph according to claim 1 incombination with an anti-tumor agent selected from the group consistingof mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, and anti-androgens.
 36. A pharmaceuticalcomposition comprising an amount of a compound according to claim 1effective to treat a hyperproliferative disorder in a mammal, and apharmaceutically acceptable carrier.
 37. The pharmaceutical compositionof claim 36, wherein the hyperproliferative disorder is a cancerselected from brain, lung, squamous cell, bladder, gastric, pancreatic,breast, head, neck, renal, kidney, ovarian, prostate, colorectal,oesophageal, gynecological and thyroid cancer.
 38. The pharmaceuticalcomposition of claim 36, wherein the composition is adapted for oraladministration.
 39. The pharmaceutical composition of claim 38, whereinthe pharmaceutical composition is in the form of a tablet.
 40. Apharmaceutical composition comprising a therapeutically effective amountof a compound of clam 1 and a pharmaceutically acceptable carrier.